EPLIN as a Molecular Target of Genistein In Preventing Prostate Cancer Metastasis Genistein, a major dietary isoflavone whose consumption is associated with reduced mortality in prostate cancer (PCa) patients, has emerged as a promising inhibitor of metastasis. Nonetheless, the mechanism of action of genistein in blocking metastatic cascade in cancer cells remains largely unknown. In this application, we will test the hypothesis that the induction of EPLIN is a crucial mechanism wherein genistein inhibits the acquisition of invasiveness by PCa cells and prevents tumor metastasis. We proposed two Specific Aims. In Aim 1, we will elucidate the molecular mechanism by which genistein upregulates EPLIN and inhibits EMT in PCa cells. The hypothesis is that genistein induces EPLIN expression at transcriptional level, thereby inhibiting EMT and suppressing invasive phenotypes. We will determine whether genistein activates EPLIN promoter by inhibiting Snail-dependent repression of EPLIN promoter. The in vitro effects of genistein on the invasiveness of PCa cells will be examined. This Aim will elucidate a novel mechanism of action of genistein in blocking the metastatic cascade in PCa cells. In Aim 2, we will determine the in vivo effects of genistein in upregulating EPLIN and preventing metastasis in pre-clinical models. The hypothesis is that in vivo administration of genistein could effectively increase EPLIN expression and significantly reduce metastatic incidence in animal models. An intracardiac model for PCa metastasis will be used to evaluate the in vivo efficacy of genistein in upregulating EPLIN, inhibiting EMT and reducing metastatic incidence. These studies will provide mechanistic basis and novel biomarkers for clinical investigation of genistein in the prevention of metastasis at early stages, therefore significantly contributing to our efforts of improving survivorship in PCa patients. PUBLIC HEALTH RELEVANCE: EPLIN as a Molecular Target of Genistein In Preventing Prostate Cancer Metastasis Metastasis is the major cause of death from prostate cancer, the most common cancer in men in Western countries. Although several new drugs are currently available for the management of metastatic disease, these therapies can only extend the median survival by approximately 3 months at high cost, which poses a huge burden on patients, their families and the healthcare system. Given the promise of genistein as a safe, efficacious and cost-effective preventive agent that could be implemented before the development of metastasis, it is imperative to understand the molecular mechanism by which genistein inhibits prostate cancer metastasis. Our application will provide mechanistic basis and novel biomarkers for clinical investigation of genistein in the prevention of metastasis at early stages, which could significantly contribute to our efforts of reducing cancer mortality and improving healthcare in the United States and globally.